Abstract
Women represent 80% of people affected by autoimmune diseases. Although, many studies have demonstrated a role for sex hormone receptor signaling, particularly estrogens, in the direct regulation of innate and adaptive components of the immune system, recent data suggest that female sex hormones are not the only cause of the female predisposition to autoimmunity. Besides sex steroid hormones, growing evidence points towards the role of X-linked genetic factors. In female mammals, one of the two X chromosomes is randomly inactivated during embryonic development, resulting in a cellular mosaicism, where about one-half of the cells in a given tissue express either the maternal X chromosome or the paternal one. X chromosome inactivation (XCI) is however not complete and 15 to 23% of genes from the inactive X chromosome (Xi) escape XCI, thereby contributing to the emergence of a female-specific heterogeneous population of cells with bi-allelic expression of some X-linked genes. Although the direct contribution of this genetic mechanism in the female susceptibility to autoimmunity still remains to be established, the cellular mosaicism resulting from XCI escape is likely to create a unique functional plasticity within female immune cells. Here, we review recent findings identifying key immune related genes that escape XCI and the relationship between gene dosage imbalance and functional responsiveness in female cells.
Highlights
Sex hormones play an indisputable role in the greater susceptibility of women to develop autoimmune diseases
It has been shown that in addition to sex hormones, X-linked genetic factors contribute to the functional plasticity of immune cells in females, suggesting that epigenetic mechanisms regulating the inactive X chromosome may have important implication in the enhanced female susceptibility to autoimmune diseases
Considering the nucleic acid sensor axis TLR7/9-IRF5-TASL, evidence exist suggesting a concerted action of sex hormones and X chromosome complement in TLR7-driven plasmacytoid dendritic cells (pDC) interferogenesis [51]
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. About 5% of the population suffers from autoimmune diseases, which is estimated to represent between 14 to 23 million people in the United States [2], of which women are the most affected category (70 to 80%). This is the case with scleroderma, rheumatoid arthritis (RA), multiple sclerosis (MS), systemic lupus erythematosus (SLE), Sjögren’s syndrome, which are three to seven times more common in women than men [3]. Understanding the genetic mechanisms by which sex chromosomes, the X chromosome, contribute to influence the strength and magnitude of immunity may, have implications, for the treatment of these immunopathological disorders, and for promoting optimal protective immunity in response to pathogens or for improving vaccine efficacy
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